Teen Vulnerability to Irritability: Brain and Estrogen Changes (TeenVIBE)

Neurobiological Mechanisms of Susceptibility to Estradiol Fluctuation in Female Adolescents at Risk of Suicide: An Experimental Approach.

Purpose: Risk of severe psychopathology increases dramatically during adolescence, especially for females. Changes in ovarian steroids across the menstrual cycle produce windows of vulnerability to mood disturbances, particularly during the abrupt withdrawal of estradiol (E2) and progesterone (P4) prior to menses onset. Irrefutable evidence links stress with affective symptoms, potentially mediated by E2-related modifications of frontolimbic connectivity and prefrontal gamma-aminobutyric acid (GABA) inhibitory signaling. The primary objective of this project is to empirically test the impact of E2 and P4 change on vulnerable brain networks associated with irritability and other depressive symptoms in female adolescents at risk of suicide.

Participants: The investigators will enroll 50 female adolescents ages 12-16 who are at risk of suicide (i.e., moderate depressive symptoms), and are eligible to receive oral contraceptives and undergo MRI imaging.

Procedure: Using a randomized, placebo-controlled, cross-over design, participants will be studied under two conditions: 8 weeks of E2 and P4 stabilization (continuous combined oral contraceptive (COC) to prevent perimenstrual withdrawal) and 8 weeks of placebo, with a 1-month washout after each condition. Each condition will include: 1) daily samples of E2 and P4 urinary metabolites, 2) daily symptom ratings(e.g., irritability, negative affect and suicidal thoughts and behaviors (STBs)), and 3) a neuroimaging session with MRI and magnetic resonance spectroscopy (MRS).

Study Overview

• Status: Not yet recruiting
• Conditions: Irritability; Depression - Major Depressive Disorder
• Intervention / Treatment: Drug: Kurvelo; Drug: Placebo COC

• Study Type: Interventional
• Enrollment (Estimated): 50
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Elizabeth Andersen, PhD; Phone Number: (919) 843-8084; Email: Elizabeth_Andersen@med.unc.edu
• Study Contact Backup: Name: Natalie Deeb; Email: nmdeeb@email.unc.edu

Study Locations

• United States
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27517
      • Biomedical Research Imaging Center (BRIC) at UNC
    • Chapel Hill, North Carolina, United States, 27517
      • Carolina Crossing
      • Contact: Elizabeth Andersen, PhD; Phone Number: 919-843-8084; Email: Elizabeth_Andersen@med.unc.edu
      • Contact: Peyton Miyares; Email: peyton_miyares@med.unc.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Assigned female sex at birth
• Between the ages of 12 and 16
• Be eligible to receive a low-dose oral contraceptive (COC)
• Post-menarche. Participants will be post-menarche to avoid potential OC-related effects on bone growth prior to menarche
• At risk of suicide. To be considered "at suicide risk" participants must meet the following-Mood and Feelings Questionnaire score of ≥ 27

Exclusion Criteria:

• Personal history of metabolic or autoimmune disease
• Epilepsy
• Endometriosis
• Cardiovascular, gastrointestinal, hepatic, renal, or pulmonary disease Diabetes mellitus with vascular disease
• Uncontrolled hypertension
• Liver tumors (benign or malignant) or liver disease
• Undiagnosed abnormal uterine bleeding
• Headaches with focal neurological symptoms or migraine with aura
• Known or suspected pregnancy
• Current or past deep vein thrombosis or pulmonary embolism
• Cerebrovascular disease Coronary artery disease
• Thrombogenic valvular or rhythm disease (e.g., subacute bacterial endocarditis with valvular disease, atrial fibrillation)
• Inherited or acquired hypercoagulopathies
• Current or history of breast cancer or other hormone-sensitive malignancy
• Use of Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir
• Personal or first-degree relative with breast cancer or thromboembolic events

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Kurvelo®, then Placebo COC; Participants will receive 8-weeks of continuous combined oral contraceptive (COC; Kurvelo®: 30mcg ethinyl estradiol (EE) and 0.15mg levonorgestrel (LNG), a synthetic estrogen and progestin, respectively). A 4-week washout period will then occur after which participants will receive 8-weeks of continuous placebo combined oral contraceptive (COC) pills.	Drug: Kurvelo; Kurvelo®: 30mcg ethinyl estradiol (EE) and 0.15mg levonorgestrel (LNG), a synthetic estrogen and progestin, respectively.; Drug: Placebo COC; Placebo pills from the Kurvelo® packages (cut from package to maintain blinding).
Placebo Comparator: Placebo COC, then Kurvelo®; Participants will receive 8-weeks of continuous placebo combined oral contraceptive (COC) pills. A 4-week washout period will then occur after which participants will receive 8-weeks of continuous combined oral contraceptive (COC; Kurvelo®: 30mcg ethinyl estradiol (EE) and 0.15mg levonorgestrel (LNG), a synthetic estrogen and progestin, respectively).	Drug: Kurvelo; Kurvelo®: 30mcg ethinyl estradiol (EE) and 0.15mg levonorgestrel (LNG), a synthetic estrogen and progestin, respectively.; Drug: Placebo COC; Placebo pills from the Kurvelo® packages (cut from package to maintain blinding).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Irritability Symptoms (average Brief Irritability Test (BITe) across each 8-week condition)	The Brief Irritability Test (BITe) is a 5-item self-report instrument developed to measure irritability as a distinct emotional construct, defined by increased susceptibility to frustration, annoyance, and anger in response to minimal provocation. Participants rate each item (e.g., feeling grumpy, easily annoyed, on edge) using a 6-point Likert scale ranging from Never (1) to Always (6). Total scores range from 5 to 30, with higher scores indicating greater irritability. BITe total score is calculated as the sum of the five items.	Average Brief Irritability Test (BITe) will be collected daily across the complete study duration (week 1 -24).

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Irritable behavior (point subtraction aggression paradigm (PSAP)	The Point Subtraction Aggression Paradigm (PSAP) is a computerized task measuring reactive aggression in response to provocation. Participants believe they compete with an opponent to earn points. They may earn points, subtract a point from the opponent (aggressive response), or activate protection. Aggression is quantified as the number of point-subtraction responses, with higher values indicating greater aggressive behavior. Scores range from 0 to the total number of opportunities/response trials within the task session, depending on task duration and provocation frequency.	During the neuroimaging session (inside the scanner) at week 8 (1 time point during the last week of condition 1) and week 20 (1 time point during the last week of condition 2)
medial prefrontal cortex GABAergic activity	Scanning will be conducted using a 7 Tesla Siemens MAGNETOM scanner (Siemens, Erlangen, Germany) with a Nova Medical 32-channel receive array head coil to obtain high-quality spectra from the medial prefrontal cortex (mPFCpref, 20 × 20 × 20 mm). The MRS voxels processed within the mPFC will be passed to the metabolite quantification process to quantify the level of gamma-aminobutyric acid (GABA).	During the neuroimaging session (inside the scanner) at week 8 (1 time point during the last week of condition 1) and week 20 (1 time point during the last week of condition 2)
Functional connectivity between amygdala and frontal network (medial, ventrolateral, ventromedial prefrontal cortex).	Connectivity strength (-1 to +1) between the amygdala and frontal network (medial, ventrolateral, ventromedial prefrontal cortex).	During the neuroimaging session (inside the scanner) at week 8 (1 time point during the last week of condition 1) and week 20 (1 time point during the last week of condition 2)

Collaborators and Investigators

• Sponsor: University of North Carolina, Chapel Hill
• Collaborators: Foundation of Hope for the Research and Treatment of Mental Illness
• Investigators: Principal Investigator: Elizabeth Andersen, PhD, University of North Carolina, Chapel Hill

Study record dates

Study Major Dates

• Study Start (Estimated): June 1, 2026
• Primary Completion (Estimated): April 1, 2028
• Study Completion (Estimated): April 1, 2029

Study Registration Dates

• First Submitted: February 2, 2026
• First Submitted That Met QC Criteria: April 15, 2026
• First Posted (Actual): April 22, 2026

Study Record Updates

• Last Update Posted (Actual): April 22, 2026
• Last Update Submitted That Met QC Criteria: April 15, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Other Study ID Numbers: 25-2243

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes